KR101007239B1 - 2-Sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of PolyADP-ribosepolymerase-1 - Google Patents

Abstract

The present invention is a 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a poly (ADP-ribose) polymerase containing the same as an active ingredient. The present invention relates to a pharmaceutical composition for preventing or treating a disease caused by overactivity of --1 (PARP-1), wherein the derivatives of the present invention consume large amounts of ATP upon overactivation, resulting in cell damage and cell death. It strongly inhibits the enzyme, PARP-1, which prevents ischemic diseases including myocardial infarction, angina pectoris, arrhythmia, heart failure, stroke, brain trauma or renal failure and neurodegenerative diseases including Parkinson's disease, Alzheimer's disease or multiple sclerosis. Or for therapeutic use, and also pharmacotherapy such as surgical therapies including coronary artery bypass surgery or coronary percutaneous plastic surgery and reperfusion therapy with thrombolytics. To be useful as cardiac protection purposes.

[Formula 1]

Wherein R ¹ , R ² , X and n are as defined in the specification.)

2-sulfanyl-benzimidazole-4-carboxamide derivatives, PARP-1 inhibitors, ischemic diseases, neurodegenerative diseases

Description

2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof, preparation method thereof and poly (AD-ribose) polymerase-1 (PARP-1) containing the same as an active ingredient Pharmaceutical composition for the prevention or treatment of diseases caused by hyperactivity {2-Sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts etc., preparation method conjugate and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of Poly (ADP-ribose) polymerase-1}

The present invention relates to a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof, a method for preparing the same, and a poly (ADP-ribose) polymerase-1 (PARP) containing the same as an active ingredient. It relates to a pharmaceutical composition for the prevention or treatment of diseases caused by overactivity of -1).

Poly (ADP-ribose) polymerase-1 (PARP-1) is an enzyme that exists in the nucleus of many organs, including the heart. It recognizes damaged DNA and activates several proteins. Poly ADP-ribosylation is an enzyme that repairs damaged DNA. The most important of the known polyADP-ribosylation substrates (acceptor or target proteins) is PARP-1 itself, and other histones, DNA topoisomerases, DNA ligase, caspase, p53 and NF- κ B and the like are known in many nuclear proteins, such as the transcription-related factor. PARP catalyzes the transfer of ADP-ribose from the NAD, where nicotinamide is released from the NAD. Nicotinamide is converted back to NAD by another enzyme, consuming ATP, the energy carrier. Thus, overactivation of PARP consumes large amounts of ATP resulting in cell damage and cell death (P. Jagtap et al., Nature Rev. Drug Discov. 2005, 4, 421).

When a cell is exposed to a substance that damages DNA, the following pathways depend on the intensity of the stimulus: First, when mild DNA damage is stimulated, PARP activated by damage stimulation interacts with DNA repair enzymes to repair damaged DNA. As a result, DNA damage is repaired and cells survive without the risk of genetic mutation. PARP inhibitors can be used as anticancer drugs because chemotherapy or radiation therapy is used in the treatment of cancer, and PARP inhibition increases the cytotoxicity of anticancer drugs because PARP is involved in repairing DNA damage. Curr. Opin. Pharmacol. 2006, 6, 364). Therefore, it has been reported to be effective as a sensitizer in tumor chemotherapy (L. Tentori et al., Pharmacol. Res. 2005, 52, 25).

Other pathways occur when DNA is severely damaged by various oxidative stresses (eg hydroxyl radicals, peroxynitrite, nitroxylanion, etc.). In this case, PARP is overactivated and consumes a lot of NAD ⁺ , resulting in a rapid consumption of ATP. In addition, depletion of NAD ⁺ , a major coenzyme of biochemical reactions in cells, inhibits glycolysis and oxidative phosphorylation of mitochondria, leading to energy depletion in cells and stopping many cell functions that require energy, resulting in cell death. Will lead to. Inhibition of PARP in cells subjected to oxidative stress preserves intracellular ATP and NAD ⁺ , resulting in normal functioning (G. Graziani et al., Pharmacol. Res. 2005, 52, 109).

Thus, inhibitors of PARP have shown remarkable protective effects in cell and animal tissues in many disease models and are known to be used for the treatment and prevention of diseases associated with increased activity of PARP by oxidative stress. Such diseases include, for example, myocardial infarction due to ischemia and reperfusion injury, renal failure, cerebral ischemia (stroke), neurodegenerative diseases (eg Parkinson's disease), diabetes, inflammatory diseases (eg arthritis), glaucoma, septic shock, immunological Diseases and the like. The therapeutic efficacy of various diseases by PARP-1 inhibition is summarized in the literature (eg L. Virag et al., Pharmacol. Rev. 2002, 54, 375 .; P. Jagtap et al., Nature Rev). Drug Discov. 2005, 4, 421).

It is described in the literature that many different classes of compounds, such as isoquinolinone, quinazolinone, phthalazine, phenantrione and pyridinone derivatives, can be used as PARP-1 inhibitors (eg, ECY Woon et. al., Curr. Med. Chem. 2005, 12, 2373). Further, the use of benzimidazole derivatives as PARP inhibitors, for example, discloses benzimidazole derivatives substituted with a quaternary carbon at 2-position in WO 2006/110816, WO WO 2007/041357 and WO 2007/131016 disclose derivatives substituted with phenyl or heteroaryl groups in the 2-position of benzimidazole, and WO 03/106430 discloses alkyl or the 2-position of benzimidazole in WO 03/106430. Benzimidazole derivatives substituted with sulfanyl groups are described.

Therefore, the present inventors have synthesized novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives while studying a drug selective for PARP-1, and these compounds selectively inhibit PARP-1 inhibitory effect. The present invention has been shown to enhance the recovery of cardiac function damage due to ischemia / reperfusion, and significantly reduce the size of myocardial infarction, thereby confirming the excellent cardioprotective effect and completing the present invention.

It is an object of the present invention to provide novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for preparing a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a poly (ADP-ribose) polymerase-1 (PARP-) containing a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a pharmaceutical composition for the prevention and treatment of diseases caused by overactivity of 1).

In order to achieve the above object, the present invention provides a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof and a poly (ADP-ribose) containing the same as an active ingredient. A pharmaceutical composition for preventing or treating a disease caused by overactivity of polymerase-1 (PARP-1) is provided.

The novel 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by the general formula (1) of the present invention recognizes and activates damaged DNA and repairs the damaged DNA through poly ADP-ribosilization of various proteins. In addition, when overactivation, a large amount of ATP is consumed, thereby showing a strong inhibitory effect on PARP-1, an enzyme that causes cell damage and cell death, thereby preventing or treating diseases caused by PARP-1 overactivity. It can be used to Specifically, the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the present invention are ischemic diseases including myocardial infarction, angina pectoris, arrhythmia, heart failure, stroke, brain trauma or kidney failure, Parkinson's disease, Alzheimer's disease It is useful for the prophylaxis or treatment of neurodegenerative diseases, including diseases or multiple sclerosis, and also for cardioprotection during pharmacotherapy such as surgery, including coronary artery bypass surgery or coronary percutaneous plastic surgery, and reperfusion therapy with thrombolytics. Can be.

Hereinafter, the present invention will be described in detail.

The present invention provides a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Chemical Formula 1,

,

,

,

,

및

로 이루어지는 군으로부터 선택되는 어느 하나이고, 이 때 R⁴는 수소, 할로겐 또는 OR³이며, R³는 위에서 정의한 바와 같고;R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, NO ₂ , CN, CF ₃ , CHO, OR ³ , C ₁ to C ₄ linear or branched alkyl and CH ₂ Y, Wherein R ³ is hydrogen or C ₁ -C ₄ straight or branched chain alkyl or CF ₃ , and Y is OR ³ , NHCH ₃ , N (CH ₃ ) ₂ ,

,

,

,

,

And

Any one selected from the group consisting of wherein R ⁴ is hydrogen, halogen or OR ³ , and R ³ is as defined above;

X is OH, OR ³ or NHR ³ ;

n is an integer of 0-2.

,

,

,

,

및

으로 이루어지는 군으로부터 선택되는 어느 하나이고, 여기에서 R⁴는 수소, 플루오로, 클로로 또는 메톡시이며;More preferably, R ¹ and R ² are each independently hydrogen, fluoro, chloro, bromo, NO ₂ , CN, CF ₃ , CHO, hydroxy, methoxy, ethoxy, -OCF ₃ , CH ₂ OH, CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ ,

,

,

,

,

And

Any one selected from the group consisting of: wherein R ⁴ is hydrogen, fluoro, chloro or methoxy;

X is any one selected from the group consisting of OH, methoxy, ethoxy, protoxy and amino;

N is an integer of 0 to 2.

Most preferred examples of the novel 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by Chemical Formula 1 according to the present invention are as follows.

(1) 2- [methoxycarbonyl (3-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(2) 2- [methoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(3) 2- [methoxycarbonyl (3-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(4) 2- [methoxycarbonyl (4-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(5) 2- [methoxycarbonyl (3-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(6) 2- [methoxycarbonyl (4-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(7) 2- [methoxycarbonyl (2-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(8) 2- [methoxycarbonyl (3-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(9) 2- [methoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(10) 2- [methoxycarbonyl (4-hydroxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(11) 2- [methoxycarbonyl (3-cyanophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(12) 2- [methoxycarbonyl (4-cyanophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(13) 2- [methoxycarbonyl [4- (trifluoromethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(14) 2- [methoxycarbonyl [4- (trifluoromethoxy) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(15) 2- [methoxycarbonyl (4-nitrophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(16) 2- [methoxycarbonyl (4-formylphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(17) 2- [methoxycarbonyl (3,4-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(18) 2- [methoxycarbonyl (2,6-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(19) 2- [methoxycarbonyl (3,5-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(20) 2- [methoxycarbonyl (4-hydroxymethylphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(21) 2- [methoxycarbonyl [(4-methylaminomethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(22) 2- [methoxycarbonyl [(4-dimethylaminomethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(23) 2- [methoxycarbonyl [(4-pyrrolidin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(24) 2- [methoxycarbonyl [(4-morpholin-4-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(25) 2- [methoxycarbonyl [(4-piperidin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(26) 2- [methoxycarbonyl [4- (4-methylpiperazin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(27) 2- [methoxycarbonyl [4- (4-phenyl-3,6-dihydro-2H-pyridin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carbox amides;

(28) 2- [methoxycarbonyl [4- [4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1 yl methyl] phenyl] methylsulfanyl] -1H-benzimidazole -4-carboxamide;

(29) 2- [methoxycarbonyl [4- (4-phenylpiperazin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(30) 2- [methoxycarbonyl [4-[(4-fluorophenyl) piperazin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(31) 2- [methoxycarbonyl [4-[(2-methoxyphenyl) piperazin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(32) 2- [methoxycarbonyl [4-[(3-methoxyphenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(33) 2- [methoxycarbonyl [4-[(2-chlorophenyl) piperazin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(34) 2- [ethoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(35) 2- [propoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(36) 2- [ethoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(37) 2- [propoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(38) 2- [carboxy (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(39) 2- [carbamoyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(40) 2- [carbamoyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide;

(41) 2- [1-methoxycarbonyl-2- (3-fluorophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(42) 2- [1-methoxycarbonyl-2- (4-fluorophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(43) 2- [1-methoxycarbonyl-2- (4-bromophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(44) 2- [1-methoxycarbonyl-2- (4-methylphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(45) 2- [1-methoxycarbonyl-2- (3-methoxyphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(46) 2- [1-methoxycarbonyl-2- (4-methoxyphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(47) 2- [1-methoxycarbonyl-2- (4-nitrophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide;

(48) 2- [1-methoxycarbonyl-2- (4-hydroxyphenyl) ethylsulfanyl] -1H-benzimidazole sol-4-carboxamide;

(49) 2- [1-methoxycarbonyl-3- (4-methoxyphenyl) propylsulfanyl] -1H-benzimidazole-4-carboxamide;

(50) 2- [1-methoxycarbonyl-3- (4-hydroxyphenyl) propylsulfanyl] -1 H-benzimidazole-4-carboxamide.

The present invention is not only a 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, and racemates that can be prepared therefrom. Or all stereoisomers in which asymmetric or chiral centers are present.

The derivative of formula 1 of the present invention may be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. These pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide De, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, meth Oxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfo Yate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a derivative of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the derivative of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

The present invention also provides a method for preparing a novel 2-sulfanyl-benzimidazole-4-carboxamide derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

Specifically, the method for preparing 2-sulfanyl-benzimidazole-4-carboxamide derivative of the present invention is shown in Scheme 1 below,

2-mercapto-1H-benzimidazole-4-carboxamide of the formula (2), which is a starting material under the reaction solvent, has a leaving group (L) and is substituted with R ¹ , R ² and X. And alkylating with an acid derivative to obtain a 2-sulfanyl-benzimidazole-4-carboxamide derivative of Formula 1 having R ¹ , R ² and X introduced therein.

In Scheme 1,

R ¹ , R ² , X and n are as defined in the general formula (1), and L is any one kind of leaving group selected from the group consisting of halogen element, mesylate and tosylate.

In the manufacturing method according to the present invention,

Since the carboxylic acid derivative (3) used in the alkylation reaction has a leaving group (L) which can be easily released, the carboxylic acid derivative (3) can be easily substituted during the reaction with the compound 2. On the other hand, the compound of Formula 3 is preferably used in 1-3 equivalents to the compound of Formula 2.

In the preparation method according to the invention, Scheme 1 is reacted under conventional alkylation conditions in the presence of a base catalyst. The base that can be used includes carbonates (e.g. sodium carbonate, potassium carbonate, cesium carbonate), hydroxides (e.g. potassium hydroxide, sodium hydroxide), hydrides (e.g. sodium hydride), alkoxides (e.g. sodium methoxide, sodium t -Butoxide) or an organic base such as triethylamine or pyridine may be used, preferably 1 to 3 equivalents. Reaction solvents include dimethylformamide, dimethyl sulfoxide, ether solvents (e.g. tetrahydrofuran, dioxane), acetone, acetonitrile, aromatic hydrocarbon compound solvents (e.g. benzene, toluene), halogenated hydrocarbon compound solvents (e.g. Dichloromethane, chloroform), water (H ₂ O), acetic acid, or the like, or a mixed solvent thereof may be used. In addition, the reaction temperature may be carried out in the temperature range of the boiling point of the solvent from room temperature.

In addition, in the preparation method according to the present invention, after performing the alkylation reaction, the substituent R1, R2 or X in the range of included in the derivative of the formula (1) according to the present invention, the reduction of aldehyde, the amination of aldehyde, deester And a step of changing the substituent by a known method such as a polymerization reaction, a synthesis reaction of an amide from an ester, and the like to prepare a 2-sulfanyl-benzimidazole-4-carboxamide derivative of the general formula (1).

As described above, the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives prepared according to the present invention are separated, purified by high performance liquid chromatography, and then subjected to molecular structure by nuclear magnetic resonance spectra and mass spectroscopy. You can check it.

Furthermore, the present invention provides poly (ADP-ribose) polymerase-1 (PARP-1) containing 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for the prevention or treatment of diseases caused by overactivity.

2-sulfanyl-benzimidazole-4-carboxamide derivatives of formula (I) of the present invention are poly (ADP-ribose) polymerase-1 (PARP-1), an enzyme that is present in the nucleus of several organs, including the heart. Inhibition (see Table 2).

When DNA is severely damaged by oxidative stress, PARP is overactive and consumes a lot of NAD +, resulting in a rapid consumption of ATP. In addition, the depletion of NAD ⁺ , a major coenzyme of biochemical reactions in cells, inhibits glycolysis and oxidative phosphorylation of mitochondria, leading to energy depletion in cells, and stopping many cell functions that require energy, resulting in cell death. This leads to. Therefore, inhibition of PARP in cells subjected to oxidative stress preserves intracellular ATP and NAD ⁺ , thereby treating or preventing diseases caused by the overactivity of PARP-1.

In addition, 2-sulfanyl-benzimidazole-4-carboxamide derivatives represented by the general formula (1) of the present invention are anti-ischemic effects in the in-vivo ischemic heart model (rat). In the measurement experiments, the results showed that the myocardial infarction rate was significantly reduced compared to the negative control group (see Table 3).

Thus, the compounds of formula 1 of the present invention can be used to prevent or treat ischemic diseases. The specific ischemic diseases include damage to the heart after cardiac ischemia (myocardial infarction, angina pectoris, arrhythmia, heart failure, etc.), brain injury after cerebral ischemia (stroke, brain trauma, etc.), kidney damage after kidney ischemia (renal failure, etc.) have.

In addition, the compounds of formula 1 of the present invention can be used to prevent or treat neurodegenerative diseases. Specific neurodegenerative diseases include Parkinson's disease, Alzheimer's disease, multiple sclerosis, and the like.

Furthermore, the compound of formula 1 of the present invention can be used for cardioprotection during surgery or pharmacotherapy. Specific surgical therapy may include coronary artery bypass surgery, coronary percutaneous plastic surgery, and drug therapy may include reperfusion therapy using thrombolytics.

In addition, the compound of formula 1 of the present invention can be used for chemotherapy for inflammation such as rheumatoid arthritis, diabetes, glaucoma, septic shock, immunological diseases, tumors and tumor metastasis.

The pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient of the present invention may be administered in various oral and parenteral dosage forms at the time of clinical administration, and is usually used when formulated. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like. Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which solid preparations comprise at least one excipient such as starch, calcium carbonate, sucrose, or the like in one or more compounds of the invention. It can be prepared by mixing (sucrose), lactose (lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.

Furthermore, the dosage of a compound of the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.1-1000 mg / day, Preferably it is 1-500 mg / day, It can also divide and administer once a day to several times at regular time intervals according to a decision of a doctor or a pharmacist.

Hereinafter, the present invention will be described in detail through Examples and Experimental Examples. These examples are for illustrating the present invention in detail, and the scope of the present invention is not limited by these examples.

Example 1: Preparation of 2- [methoxycarbonyl (3-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

2-mercapto-1H-benzimidazole-4-carboxamide (200 mg, 1.04 mmol) and methyl α-bromo-3-bromophenylacetate (320 mg, 1.04 mmol) were added to dimethylformamide (3 mL). ), K ₂ CO ₃ (216 mg, 1.56 mmol) was added thereto, and reacted at 40 ° C. for 10 minutes. H ₂ O (20 mL) was added, extracted with ethyl acetate (20 mL) and washed with aqueous NaCl solution. The organic layer was dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (5% methanol / dichloromethane) to give 229 mg (0.55 mmol, 52%) of the title compound as a yellow solid.

Rf = 0.35 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.68 (s, 3H), 3.76 (s, 3H), 5.76 (d, 1H), 6.98 (d, 2H), 7.22 (dd, 1H), 7.48 (d, 2H), 7.59 (d, 1H) , 7.76 (d, 1 H), 7.77 (br-s, 1 H), 8.92 (br-s, 1 H)

mass: 371, 339, 179

Example 2: Preparation of 2- [methoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same procedure as in Example 1 except that methyl α-bromo-4-bromophenyl acetate (320 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. Reaction was carried out to give 250 mg (0.60 mmol, 58%) of the title compound as a yellow solid.

Rf = 0.2 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.82 (s, 3H), 6.03 (s, 1H), 7.39 (dd, 1H), 7.67 (m, 5H), 7.92 (d, 2H), 8.99 (br- s, 1H), 13.3 (br-s, 1H)

mass: 420, 388

Example 3: Preparation of 2- [methoxycarbonyl (3-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same procedure as in Example 1 except that methyl α-bromo-3-fluorophenylacetate (257 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. The reaction was carried out to give 243 mg (0.68 mmol, 65%) of the title compound as a yellow solid.

Rf = 0.39 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.70 (s, 3H), 5.92 (s, 1H), 7.25 (m, 2H), 7.48 (m, 3H), 7.60 (d, 1H), 7.80 (m, 2H), 8.87 (br-s, 1H)

mass: 359, 327

Example 4: Preparation of 2- [methoxycarbonyl (4-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same procedure as in Example 1 except that methyl α-bromo-4-fluorophenylacetate (306 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. Reaction was carried out to give 283 mg (0.79 mmol, 76%) of the title compound as a yellow solid.

Rf = 0.36 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 3.70 (s, 3H), 5.90 (s, 1H), 7.24 (m, 3H), 7.63 (m, 3H), 7.84 (m, 2H), 8.89 (br-s, 1H), 13.16 (br- s, 1 H)

mass: 359, 327

Example 5: Preparation of 2- [methoxycarbonyl (3-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same method as in Example 1, except that methyl α-bromo-3-chlorophenyl acetate (274 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. Reaction was carried out to give 266 mg (0.71 mmol, 68%) of the title compound as a yellow solid.

Rf = 0.13 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.72 (s, 3H), 5.94 (s, 1H), 7.27 (t, 1H), 7.48 (m, 2H), 7.54 (m, 1H), 7.60 (d, 1H), 7.67 (s, 1H), 7.79 (m, 2H), 8.87 (br-s, 1H), 13.19 (br-s, 1H)

mass: 375, 343

Example 6: Preparation of 2- [methoxycarbonyl (4-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

100 mg (0.52 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and the use of methyl α-bromo-3-chlorophenylacetate instead. 117 mg (0.31 mmol, 60%) of the target compound as a yellow solid by the same method as in Example 1 except that methyl α-bromo-4-chlorophenyl acetate (163 mg, 0.62 mmol) was used. Got.

Rf = 0.4 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 3.71 (s, 3H), 5.92 (s, 1H), 7.26 (dd, 1H), 7.48 (d, 2H), 7.60 (m, 3H), 8.86 (br-s, 1H), 13.18 (br- s, 1 H)

mass: 375, 343

Example 7: Preparation of 2- [methoxycarbonyl (2-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

100 mg (0.52 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and the use of methyl α-bromo-3-chlorophenylacetate instead. 100 mg (0.27 mmol, 52% of the target compound as a yellow solid) was reacted in the same manner as in Example 1, except that methyl α-bromo-2-methoxyphenyl acetate (135 mg, 0.52 mmol) was used. )

Rf = 0.23 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.68 (s, 3H), 3.85 (s, 3H), 6.10 (s, 1H), 6.99 (t, 1H), 7.10 (d, 1H), 7.26 (t, 1H), 7.41 (m, 2H), 7.58 (d, 1H), 7.80 (m, 2H), 8.93 (br-s, 1H), 13.17 (br-s, 1H)

mass: 371, 339

Example 8: Preparation of 2- [methoxycarbonyl (3-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same procedure as in Example 1 except that methyl α-bromo-3-methoxyphenylacetate (270 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. Reaction was carried out to give 161 mg (0.43 mmol, 42%) of the title compound as a yellow solid.

Rf = 0.16 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.71 (s, 3H), 3.78 (s, 3H), 5.84 (s, 1H), 7.00 (d, 1H), 7.13 (m, 2H), 7.28 (dd, 1H), 7.37 (dd, 1H) , 7.61 (d, 1H), 7.82 (d, 1H), 7.87 (br-s, 1H), 8.92 (br-s, 1H)

mass: 371, 339, 296

Example 9: Preparation of 2- [methoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

100 mg (0.52 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and the use of methyl α-bromo-3-chlorophenylacetate instead. 172 mg (0.46 mmol, 89%) of the target compound as a yellow solid by the same method as in Example 1, except that methyl α-bromo-4-methoxyphenyl acetate (161 mg, 0.62 mmol) was used. )

Rf = 0.35 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.68 (s, 3H), 3.76 (s, 3H), 5.76 (d, 1H), 6.98 (d, 2H), 7.22 (dd, 1H), 7.48 (d, 2H), 7.59 (d, 1H) , 7.76 (d, 1 H), 7.77 (br-s, 1 H), 8.92 (br-s, 1 H)

mass: 371, 339, 179

Example 10 Preparation of 2- [methoxycarbonyl (4-hydroxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Example 1 The same procedure as in Example 1 except that methyl α-bromo-4-hydroxyphenyl acetate (255 mg, 1.04 mmol) was used instead of methyl α-bromo-3-bromophenyl acetate. Reaction was carried out to give 182 mg (0.51 mmol, 49%) of the title compound as a yellow solid.

Rf = 0.07 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.67 (s, 3H), 5.70 (s, 1H), 6.79 (d, 2H), 7.26 (dd, 1H), 7.36 (d, 2H), 7.60 (d, 1H), 7.78 (d, 1H), 7.81 (br-s, 1H), 8.92 (br-s, 1H), 9.73 (br-s, 1H), 13.1 (br-s, 1H)

mass: 357, 193

Example  11: 2- [methoxycarbonyl (3- Cyanophenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate 97 mg (0.26 mmol, 73% of the target compound as a yellow solid) was reacted in the same manner as in Example 1, except that methyl α-bromo-3-cyanophenyl acetate (102 mg, 0.36 mmol) was used. )

Rf = 0.21 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) delta = 3.72 (s, 3H), 6.03 (s, 1H), 7.26 (dd, 1H), 7.64 (m, 2H), 7.88 (m, 4H), 8.03 (s, 1H), 8.86 (br-s, 1H)

mass: 368

Example  12: 2- [methoxycarbonyl (4- Cyanophenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

100 mg (0.52 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and the use of methyl α-bromo-3-chlorophenylacetate instead. 131 mg (0.36 mmol, 69%) of the target compound as a yellow solid by the same method as Example 1 except that methyl α-bromo-4-cyanophenyl acetate (132 mg, 0.52 mmol) was used. )

Rf = 0.25 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.53 (s, 3H), 5.88 (s, 1H), 7.08 (t, 1H), 7.43 (d, 1H), 7.60 (m, 3H), 7.72 (m, 3H), 8.65 (br-s, 1H), 13.02 (br-s, 1H)

mass: 366, 334

Example  13: 2- [methoxycarbonyl [4- ( Trifluoromethyl ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, 49 mg (0.25 mmol) was used instead of methyl α-bromo-3-chlorophenylacetate. 71 mg (0.17) of the title compound as a yellow solid was reacted in the same manner as in Example 1, except that methyl α-bromo-4- (trifluoromethyl) phenyl acetate (76 mg, 0.25 mmol) was used. mmol, 70%).

Rf = 0.23 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.72 (s, 3H), 6.05 (s, 1H), 7.26 (dd, 1H), 7.60 (d, 1H), 7.86 (m, 6H), 8.82 (br- s, 1H), 13.22 (br-s, 1H)

mass: 409,332

Example  14: 2- [methoxycarbonyl [4- ( Trifluoromethoxy ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, 49 mg (0.25 mmol) was used instead of methyl α-bromo-3-chlorophenylacetate. 82 mg (0.19) of the title compound as a yellow solid was reacted in the same manner as in Example 1, except that methyl α-bromo-4- (trifluoromethoxy) phenylacetate (79 mg, 0.25 mmol) was used. mmol, 77%).

Rf = 0.22 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.71 (s, 3H), 5.98 (s, 1H), 7.28 (dd, 1H), 7.45 (d, 2H), 7.61 (d, 1H), 7.68 (d, 2H), 7.74 (d, 1H), 7.89 (br-s, 1H), 8.89 (br-s, 1H), 13.22 (br-s, 1H)

mass: 425, 393

Example  15: 2- [methoxycarbonyl (4- Nitrophenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate 95 mg (0.25 mmol, 68%) of the target compound as a yellow solid was reacted in the same manner as in Example 1, except that methyl α-bromo-4-nitrophenyl acetate (110 mg, 0.36 mmol) was used. Got.

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.72 (s, 3H), 6.14 (s, 1H), 7.27 (dd, 1H), 7.58 (d, 1H), 7.80 (m, 2H), 7.86 (d, 2H), 8.26 (d, 2H) , 8.83 (br-s, 1 H), 13.21 (br-s, 1 H)

mass: 386, 354

Example  16: 2- [methoxycarbonyl (4- Formylphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 114 mg (0.59 mmol) and methyl α-bromo-3-chlorophenylacetate instead. 157 mg (0.43 mmol, 72%) of the target compound as a yellow solid was reacted in the same manner as in Example 1, except that methyl α-bromo-4-formylphenyl acetate (110 mg, 0.36 mmol) was used. Got.

Rf = 0.21 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.72 (s, 3H), 6.04 (s, 1H), 7.25 (dd, 1H), 7.59 (d, 1H), 7.80 (m, 4H), 7.95 (d, 2H), 8.98 (br-s, 1H), 10.01 (s, 1H), 13.23 (br-s, 1H)

mass: 369, 337

Example  17: 2- [methoxycarbonyl (3,4- Dimethoxyphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

100 mg (0.52 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and the use of methyl α-bromo-3-chlorophenylacetate instead. 168 mg (0.42 mmol,) of the target compound as a yellow solid, except that methyl α-bromo-3,4-dimethoxyphenylacetate (150 mg, 0.52 mmol) was used in the same manner as in Example 1. 80%).

Rf = 0.22 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.69 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 5.77 (s, 1H), 6.96 (d, 1H), 7.08 (d, 1H), 7.19 (s, 1H) , 7.26 (dd, 1H), 7.59 (d, 1H, J = 8.1 Hz), 7.79 (br-s, 1H), 7.83 (d, 1H, J = 8.1 Hz), 8.94 (br-s, 1H), 13.13 (br-s, 1 H)

mass: 401, 369

Example  18: 2- [methoxycarbonyl (2,6- Dimethoxyphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Ka Preparation of Leboxamide

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate In the same manner as in Example 1, except that methyl α-bromo-2,6-dimethoxyphenylacetate (105 mg, 0.36 mmol) was used, 116 mg (0.29 mmol, 80%).

Rf = 0.21 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.68 (s, 6H), 3.79 (s, 3H), 6.08 (s, 1H), 6.96 (m, 2H), 7.03 (d, 1H), 7.25 (dd, 1H), 7.58 (d, 1H) , 7.79 (m, 2H), 9.27 (br-s, 1H), 13.08 (br-s, 1H)

mass: 401, 369

Example  19: 2- [methoxycarbonyl (3,5- Dimethoxyphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, 43 mg (0.23 mmol) was used instead of methyl α-bromo-3-chlorophenylacetate. 80 mg (0.20 mmol, of the title compound as a yellow solid) was reacted in the same manner as in Example 1, except that methyl α-bromo-3,5-dimethoxyphenylacetate (67 mg, 0.23 mmol) was used. 86%).

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.70 (s, 3H), 3.75 (s, 6H), 5.76 (s, 2H), 6.53 (s, 1H), 6.72 (m, 2H), 7.26 (dd, 1H), 7.60 (d, 1H) , 7.79 (d, 1H), 7.85 (br-s, 1H), 8.92 (br-s, 1H), 13.14 (br-s, 1H)

mass: 401, 369

Example  20: 2- [methoxycarbonyl (4- Hydroxymethylphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound obtained in Example 16 (100 mg, 0.27 mmol) was dissolved in methanol (3 mL), NaBH ₄ (20 mg, 0.54 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Then, the solvent was removed and purified by silica gel column chromatography (5% methanol / dichloromethane) to give 81 mg (0.22 mmol, 80%) of the target compound as a yellow solid.

Rf = 0.12 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.69 (s, 3H), 4.49 (d, 2H), 5.24 (t, 1H), 5.83 (s, 1H), 7.26 (dd, 1H), 7.35 (d, 2H), 7.52 (d, 2H), 7.60 (d, 1H), 7.80 (d, 1H), 7.85 (br-s, 1H), 8.92 (br-s, 1H), 13.15 (br-s, 1H)

mass: 371, 339

Example  21: 2- [methoxycarbonyl [(4- Methylaminomethyl ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound (100 mg, 0.27 mmol) obtained in Example 16 was dissolved in methanol (5 mL), and methylamine hydrochloride (28 mg, 0.41 mmol) and triethylamine (57 μL, 0.41 mmol) were added for 2 hours. It was heated to reflux. Then, sodium borohydride (20 mg, 0.54 mmol) was added at room temperature and stirred for 1 hour. The solvent was concentrated by distillation under reduced pressure and purified by silica gel column chromatography (20% methanol / dichloromethane) to obtain 59 mg (0.15 mmol, 57%) of the title compound as a pale yellow solid.

Rf = 0.17 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.53 (s, 3H), 3.70 (s, 3H), 4.10 (s, 2H), 5.92 (s, 1H), 7.26 (dd, 1H), 7.58 (m, 5H), 7.78 (d, 1H), 7.81 (br-s, 1H), 8.88 (br-s, 1H)

mass: 385 (+1)

Example  22: 2- [methoxycarbonyl [(4- Dimethylaminomethyl ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Using the compound (100 mg, 0.27 mmol) obtained in Example 16 and dimethylamine hydrochloride (33 mg, 0.41 mmol) in the same manner as in Example 21, 39 mg (0.10 mmol) of the target compound as a pale yellow solid was obtained. , 37%).

Rf = 0.16 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.47 (s, 6H), 3.70 (s, 3H), 3.94 (s, 2H), 5.89 (s, 1H), 7.24 (dd, 1H), 7.50 (d, 2H), 7.62 (m, 3H), 7.80 (d, 1H), 7.85 (br-s, 1H), 8.89 (br-s, 1H), 13.20 (br-s, 1H)

mass: 398

Example  23: 2- [methoxycarbonyl [(4- Pyrrolidine -One- Yl methyl ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound (100 mg, 0.27 mmol) obtained in Example 16 was dissolved in MeOH (5 mL), and pyrrolidine (34 μL, 0.41 mmol) was added thereto, followed by heating to reflux for 2 hours. After cooling to room temperature, sodium borohydride (20 mg, 0.54 mmol) was added thereto, stirred for 1 hour, the solvent was distilled off under reduced pressure, concentrated and purified by silica gel column chromatography (10% methanol / dichloromethane) to obtain a pale yellow solid. 77 mg (0.18 mmol, 67%) of the title compound were obtained.

Rf = 0.13 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.63 (m, 4H), 2.23 (m, 4H), 3.52 (s, 2H), 3.63 (s, 3H), 5.69 (s, 1H), 7.19 (dd, 1H), 7.28 (d, 2H), 7.43 (d, 2H), 7.53 (d, 1H), 7.71 (d, 1H), 7.74 (br-s, 1H), 8.84 (br-s, 1H), 13.11 (br-s, 1H)

mass: 392 (-32), 323

Example  24: 2- [methoxycarbonyl [(4- Morpholine -4- Yl methyl ) Phenyl ] Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Using the compound obtained in Example 16 (100 mg, 0.27 mmol) and morpholine (36 μL, 0.41 mmol) in the same manner as in Example 23, 69 mg (0.16 mmol, 58%) of the title compound as a white solid were obtained. )

Rf = 0.42 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.34 (m, 4H), 3.42 (s, 2H), 3.57 (m, 4H), 3.69 (s, 3H), 5.83 (s, 1H), 7.27 (dd, 1H), 7.37 (d, 2H), 7.52 (d, 2H), 7.60 (d, 1H), 7.78 (d, 1H), 7.84 (br-s, 1H), 8.91 (br-s, 1H), 13.15 (br-s, 1H)

mass: 440

Example 25 Preparation of 2- [methoxycarbonyl [(4-piperidin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

Using the compound obtained in Example 16 (100 mg, 0.27 mmol) and piperidine (40.5 μL, 0.41 mmol) in the same manner as in Example 23, 97 mg (0.16 mmol, 82%).

Rf = 0.13 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.39 (m, 2H), 1.49 (m, 4H), 2.31 (m, 4H), 3.42 (s, 2H), 3.69 (s, 3H), 5.82 (s, 1H), 7.27 (dd, 1H), 7.33 (d, 2H), 7.50 (d, 2H), 7.60 (d, 1H), 7.78 (d, 1H), 7.81 (br-s, 1H), 8.99 (br -s, 1H), 13.09 (br-s, 1H)

mass: 439 (+1), 406 (-32)

Example 26 Preparation of 2- [methoxycarbonyl [4- (4-methylpiperazin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

Using the compound (100 mg, 0.27 mmol) obtained in Example 16 and 1-methylpiperazine (45.6 μL, 0.41 mmol) in the same manner as in Example 23, 67 mg (0.15) of the target compound as a pale yellow solid was obtained. mmol, 55%).

Rf = 0.11 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.15 (s, 3H), 2.34 (m, 8H), 3.45 (s, 2H), 3.69 (s, 3H), 5.82 (s, 1H), 7.25 (dd, 1H), 7.34 (d, 2H), 7.50 (d, 2H), 7.60 (d, 1H), 7.78 (d, 1H), 7.86 (br-s, 1H), 8.99 (br-s, 1H)

Example 27: 2- [methoxycarbonyl [4- (4-phenyl-3,6-dihydro-2H-pyridin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-car Preparation of Voxamide

Reaction in the same manner as in Example 21, using the compound (100 mg, 0.27 mmol) obtained in Example 16 and 4-phenyl-1.2,3,6, -tetrahydropyridine hydrochloride (33 mg, 0.41 mmol). To obtain 75.7 mg (0.15 mmol, 55%) of the title compound as a pale yellow solid.

Rf = 0.26 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.50 (m, 2H), 2.65 (m, 2H), 3.06 (m, 2H), 3.60 (s, 2H), 3.70 (s, 3H), 5.84 (s, 1H), 6.14 (t, 1H), 7.25 (m, 3H), 7.26-7.44 (m, 5H), 7.53 (d, 2H), 7.60 (d, 1H), 7.80 (d, 1H), 7.81 (br) -s, 1H), 8.92 (br-s, 1H), 13.13 (br-s, 1H)

mass: 512, 159

Example 28: 2- [methoxycarbonyl [4- [4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimi Preparation of Dazole-4-carboxamide

Example 21 using the compound obtained in Example 16 (100 mg, 0.27 mmol) and 4- (4-chlorophenyl) -1.2,3,6, -tetrahydropyridine hydrochloride (94 mg, 0.41 mmol) In the same manner as the reaction compound 48 mg (0.09 mmol, 32%) of the title compound as a light yellow solid.

Rf = 0.33 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.44 (m, 2H), 2.61 (m, 2H), 3.04 (m, 2H), 3.57 (s, 2H), 3.65 (s, 3H), 5.81 (s, 1H), 6.12 (t, 1H), 7.21 (dd, 1H), 744 (m, 6H), 7.50 (d, 2H), 7.53 (d, 1H), 7.72 (d, 1H), 7.76 (br-s , 1H), 8.94 (br-s, 1H)

mass: 547, 355, 323

Example 29 Preparation of 2- [methoxycarbonyl [4- (4-phenylpiperazin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

75 mg (0.15) of the target compound as a pale yellow solid was reacted in the same manner as in Example 23, using the compound (100 mg, 0.27 mmol) and 1-phenylpiperazine (62 μL, 0.41 mmol) obtained in Example 16. mmol, 54%).

Rf = 0.20 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.14 (m, 4H), 3.31 (m, 4H), 3.51 (s, 2H), 3.68 (s, 3H), 5.82 (s, 1H), 6.74 (t, 1H), 6.91 (d, 2H), 7.21 (m, 3H), 7.25 (d, 2H), 7.53 (m, 2H), 7.58 (d, 1H), 7.78 (d, 1H), 7.83 (br-s , 1H), 8.89 (br-s, 1H), 13.13 (br-s, 1H)

mass: 515

Example 30 Preparation of 2- [methoxycarbonyl [4-[(4-fluorophenyl) piperazin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

The compound obtained in Example 16 (100 mg, 0.27 mmol) and 1- (4-fluorophenyl) piperazine (73.9 mg, 0.41 mmol) were reacted in the same manner as in Example 23 to obtain a pale yellow solid. 50 mg (0.10 mmol, 35%) of the title compound was obtained.

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.07 (m, 4H), 3.30 (m, 4H), 3.52 (s, 2H), 3.69 (s, 3H), 5.84 (s, 1H), 6.92 (m, 2H), 7.04 (m, 2H), 7.26 (dd, 1H), 7.38 (d, 2H), 7.53 (d, 2H), 7.60 (d, 1H), 7.78 (d, 1H), 7.80 (br-s , 1H), 8.92 (br-s, 1H), 13.09 (br-s, 1H)

mass: 533, 180

Example 31 Preparation of 2- [methoxycarbonyl [4-[(2-methoxyphenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

The compound obtained in Example 16 (100 mg, 0.27 mmol) and 1- (2-methoxyphenyl) piperazine (78.8 mg, 0.41 mmol) were reacted in the same manner as in Example 23 to obtain a pale yellow solid. 60 mg (0.11 mmol, 41%) of the title compound were obtained.

Rf = 0.16 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.76 (m, 4H), 3.11 (m, 4H), 3.33 (s, 2H), 3.51 (s, 3H), 3.56 (s, 3H), 6.56 (s, 1H), 6.73 (m, 4H), 7.07 (dd, 1H), 7.19 (d, 2H), 7.34 (d, 2H), 7.40 (d, 1H), 7.59 (d, 1H), 7.62 (br-s , 1H), 8.72 (br-s, 1H), 12.93 (br-s, 1H)

mass: 545, 175

Example 32 Preparation of 2- [methoxycarbonyl [4-[(3-methoxyphenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

The compound obtained in Example 16 (100 mg, 0.27 mmol) and 1- (3-methoxyphenyl) piperazine (70.8 μL, 0.41 mmol) were reacted in the same manner as in Example 23 to obtain a pale yellow solid. 34 mg (0.063 mmol, 23%) of the title compound was obtained.

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.12 (m, 4H), 3.30 (m, 4H), 3.52 (s, 2H), 3.70 (s, 6H), 5.84 (s, 1H), 6.36 (d, 1H), 6.43 (s, 1H), 6.49 (d, 1H), 7.09 (t, 1H), 7.27 (dd, 1H), 7.38 (d, 2H), 7.54 (d, 2H), 7.60 (d, 1H ), 7.79 (d, 1H), 7.82 (br-s, 1H), 8.91 (br-s, 1H), 13.16 (br-s, 1H)

mass: 545, 175

Example 33 Preparation of 2- [methoxycarbonyl [4-[(2-chlorophenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide

Using the compound (100 mg, 0.27 mmol) obtained in Example 16 and 1- (1-chlorophenyl) piperazine (96 mg, 0.41 mmol) in the same manner as in Example 23, the purpose of the pale yellow solid 77 mg (0.14 mmol, 52%) were obtained.

Rf = 0.17 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.54 (m, 4H), 2.98 (m, 4H), 3.55 (s, 2H), 3.70 (s, 3H), 5.84 (s, 1H), 7.03 (dd, 1H), 7.15 (d, 1H), 7.27 (m, 2H), 7.39 (m, 3H), 7.53 (d, 2H), 7.58 (d, 1H), 7.80 (d, 1H), 7.82 (br-s , 1H), 8.93 (br-s, 1H), 13.10 (br-s, 1H)

mass: 550

Example 34 Preparation of 2- [ethoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate 93 mg (0.24 mmol, 67) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that ethyl α-bromo-3-bromophenyl acetate (109 mg, 0.40 mmol) was used. %) Was obtained.

Rf = 0.08 (2% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 0.70 (t, 3H), 1.52 (q, 2H), 3.76 (s, 3H), 4.08 (m, 2H), 5.78 (s, 1H), 6.98 (d, 2H), 7.25 (dd, 1H), 7.48 (d, 2H), 7.59 (d, 1H), 7.78 (m, 2H), 8.89 (br-s, 1H), 13.12 (br-s, 1H)

mass: 399, 339, 207

Example 35 Preparation of 2- [propoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate 118 mg (0.26 mmol, 82) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1 except for using propyl α-bromo-3-bromophenyl acetate (115 mg, 0.40 mmol). %) Was obtained.

Rf = 0.08 (2% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 0.70 (t, 3H), 1.52 (q, 2H), 3.76 (s, 3H), 4.08 (m, 2H), 5.78 (s, 1H), 6.98 (d, 2H), 7.25 (dd, 1H), 7.48 (d, 2H), 7.59 (d, 1H), 7.78 (m, 2H), 8.89 (br-s, 1H), 13.12 (br-s, 1H)

mass: 399, 339, 207

Example 36 Preparation of 2- [ethoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate 150 mg (0.35 mmol, 96) of the target compound as a pale yellow solid was reacted in the same manner as in Example 1, except that ethyl α-bromo-4-bromophenyl acetate (129 mg, 0.40 mmol) was used. %) Was obtained.

Rf = 0.12 (2% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 1.13 (t, 3H), 4.15 (m, 2H), 5.88 (s, 1H), 7.26 (dd, 1H), 7.53 (d, 2H), 7.62 (m, 2H), 7.81 (m, 2H), 8.88 (br-s, 1H)

mass: 435

Example 37 Preparation of 2- [propoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 70 mg (0.36 mmol) and methyl α-bromo-3-chlorophenyl acetate Reaction with the same method as in Example 1, except that Epropyl α-bromo-4-bromophenyl acetate (135 mg, 0.40 mmol) was used to give 112 mg (0.25 mmol, 70) of the target compound as a pale yellow solid. %) Was obtained.

Rf = 0.15 (2% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 0.69 (t, 3H), 1.53 (q, 2H), 4.07 (m, 2H), 5.89 (s, 1H), 7.26 (dd, 1H), 7.53 (d, 2H), 7.65 (m, 3H), 7.77 (m, 2H), 8.86 (br-s, 1H)

mass: 449

Example 38 Preparation of 2- [carboxy (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide

The compound obtained in Example 9 (200 mg, 0.54 mmol) was dissolved in THF (3 mL), 6N-NaOH solution (1.5 mL) was added, and the mixture was heated to reflux for 1 hour. After cooling, 3N-HCl (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL) and washed with an aqueous NaCl solution. The organic layer was dried over MgSO ₄ and concentrated to give 171 mg (0.48 mmol, 89%) of the title compound as a yellow solid.

Rf = 0.17 (20% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.75 (s, 3H), 5.67 (s, 1H), 6.95 (d, 2H, J = 8.3 Hz), 7.24 (dd, 1H), 7.48 (d, 2H, J = 8.3 Hz), 7.58 (d, 1H, J = 7.6 Hz), 7.68 (br-s, 1H), 7.76 (d, 1H, J = 7.6 Hz), 8.94 (br-s, 1H), 13.08 ( br-s, 1 H)

mass: 339 (-18)

Example  39: 2- [carbamoyl (4- Methoxyphenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound (100 mg, 0.27 mmol) obtained in Example 9 was dissolved in ethanol (3 mL), and ammonia water (3 mL) was added thereto, and the mixture was heated and stirred at 70 ° C. for 2 hours. The solid produced by distillation of the solvent under reduced pressure was filtered and then washed with dichloromethane (10 mL). After drying under reduced pressure, 67 mg (0.19 mmol, 69%) of the title compound was obtained as a light yellow solid.

Rf = 0.29 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.72 (s, 3H), 5.71 (s, 1H), 6.90 (d, 2H), 7.22 (dd, 1H), 7.28 (br-s, 1H), 7.50 ( m, 3H), 7.76 (m, 2H), 7.93 (br-s, 1H), 9.01 (br-s, 1H), 13.02 (br-s, 1H)

mass: 356, 339

Example  40: 2- [carbamoyl (4- Bromophenyl ) Methylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

The compound (132 mg, 0.30 mmol) obtained in Example 36 was reacted in the same manner as in Example 39, to obtain 95.4 mg (0.24 mmol, 78%) of the title compound as a light yellow solid.

Rf = 0.37 (10% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 5.77 (s, 1H), 7.20 (m, 2H), 7.41 (s, 1H), 7.53 (m, 3H), 7.73 (m, 3H), 8.02 (br- s, 1H), 8.94 (br-s, 1H), 13.09 (br-s, 1H)

mass: 406, 389

Example  41: 2- [1- Methoxycarbonyl -2- (3- Fluorophenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

129 mg (0.67 mmol) was used instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and instead of methyl α-bromo-3-chlorophenylacetate. 154 mg of the target compound as a white solid was reacted in the same manner as in Example 1, except that 2-bromo-3- (3-fluorophenyl) propionic acid methyl ester (175 mg, 0.67 mmol) was used. 0.41 mmol, 61%).

Rf = 0.20 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.25 (m, 2H), 3.61 (s, 3H), 4.79 (t, 1H), 7.14 (m, 3H), 7.26 (dd, 1H), 7.34 (m, 1H), 7.58 (d, 1H), 7.78 (br-s, 1H), 7.80 (d, 1H), 8.88 (br-s, 1H), 13.11 (br-s, 1H)

mass: 373, 341

Example  42: 2- [1- Methoxycarbonyl -2- (4- Fluorophenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, use 140 mg (0.72 mmol) and methyl α-bromo-3-chlorophenylacetate instead. In the same manner as in Example 1, except that 2-bromo-3- (4-fluorophenyl) propionic acid methyl ester (190 mg, 0.72 mmol) was used, 113 mg of the target compound as a white solid ( 0.30 mmol, 42%).

Rf = 0.24 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.26 (m, 2H), 3.60 (s, 3H), 4.75 (t, 1H), 7.14 (m, 2H), 7.28 (m, 3H), 7.57 (d, 2H), 7.78 (d, 1H), 7.80 (br-s, 1H), 8.88 (br-s, 1H)

mass: 374 (+1), 341

Example  43: 2- [1- Methoxycarbonyl -2- (4- Bromophenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, using 72 mg (0.37 mmol) and methyl α-bromo-3-chlorophenylacetate instead. 74 mg of the target compound as a white solid was reacted in the same manner as in Example 1, except that 2-bromo-3- (4-bromophenyl) propionic acid methyl ester (120 mg, 0.37 mmol) was used. 0.10 mmol, 46%).

Rf = 0.25 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.28 (m, 2H), 3.61 (s, 3H), 4.77 (t, 1H), 7.25 (m, 3H), 7.50 (d, 2H), 7.58 (d, 1H), 7.77 (br-s, 1H), 7.79 (d, 1H), 8.88 (br-s, 1H), 13.11 (br-s, 1H)

mass: 434

Example  44: 2- [1- Methoxycarbonyl -2- (4- Methylphenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

177 mg (0.91 mmol) was used instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and methyl-bromo-3-chlorophenylacetate instead. 179 mg (0.49 mmol, of white solid) as a target compound in the same manner as in Example 1, except that 2-bromo-3- (4-methylphenyl) propionic acid methyl ester (235 mg, 0.91 mmol) was used. 53%).

¹ H-NMR (300 MHz, DMSO) δ = 2.27 (s, 3H), 3.15 (m, 2H), 3.59 (s, 3H), 4.72 (t, 1H), 7.13 (m, 4H), 7.25 (dd, 1H), 7.57 (d, 1H), 7.78 (br-s, 1H), 7.80 (d, 1H), 8.89 (br-s, 1H), 13.10 (br-s, 1H)

mass: 369, 336

Example  45: 2- [1- Methoxycarbonyl -2- (3- Methoxyphenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Use 81 mg (0.42 mmol) instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and use methyl α-bromo-3-chlorophenylacetate instead. 74 mg (0.19) of the target compound as a white solid was reacted in the same manner as in Example 1, except that 2-bromo-3- (3-methoxyphenyl) propionic acid methyl ester (118 mg, 0.42 mmol) was used. mmol, 46%).

Rf = 0.25 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.19 (m, 2H), 3.60 (s, 3H), 3.72 (s, 3H), 4.78 (t, 1H), 6.82 (m, 3H), 7.25 (m, 2H), 7.58 (d, 1H), 7.76 (br-s, 1H), 7.78 (d, 1H), 8.89 (br-s, 1H), 13.10 (br-s, 1H)

mass: 385, 352

Example  46: 2- [1- Methoxycarbonyl -2- (4- Methoxyphenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

260 mg (1.35 mmol) was used instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and methyl-bromo-3-chlorophenylacetate was used instead. 309 mg of the target compound as a white solid was reacted in the same manner as in Example 1, except that 2-bromo-3- (4-methoxyphenyl) propionic acid methyl ester (370 mg, 1.35 mmol) was used. 0.80 mmol, 59%).

Rf = 0.35 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.17 (m, 2H), 3.60 (s, 3H), 3.71 (s, 3H), 4.71 (m, 1H), 6.87 (d, 2H), 7.18 (d, 2H), 7.25 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 7.79 (br-s, 1H), 8.90 (br-s, 1H), 13.1 (br-s, 1H)

mass: 385

Example  47: 2- [1- Methoxycarbonyl -2- (4- Nitrophenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, 47 mg (0.24 mmol) was used instead of methyl α-bromo-3-chlorophenylacetate. 24 mg (0.06) of the target compound as a white solid was reacted in the same manner as in Example 1, except that 2-bromo-3- (4-nitrophenyl) propionic acid methyl ester (70 mg, 0.24 mmol) was used. mmol, 25%).

Rf = 0.28 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.39 (m, 1H), 3.50 (m, 1H), 3.63 (s, 3H), 4.88 (t, 1H), 7.26 (dd, 1H), 7.59 (m, 3H), 7.78 (d, 1H), 7.81 (br-s, 1H), 8.16 (d, 2H), 8.85 (br-s, 1H), 13.13 (br-s, 1H)

mass: 400, 367

Example  48: 2- [1- Methoxycarbonyl -2- (4- Hydroxyphenyl ) Ethylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, use 104 mg (0.54 mmol) and instead of methyl α-bromo-3-chlorophenylacetate Was reacted in the same manner as in Example 1, except that 2-bromo-3- [4- (t-butyldimethylsilyloxy) phenyl] propionic acid methyl ester (200 mg, 0.54 mmol) was used. 134 mg (0.28 mmol, 51%) of the title compound were obtained.

The compound obtained above (120 mg, 0.25 mol) was dissolved in purified THF (3 mL), and tetrabutylammonium fluoride (1M in THF) (0.14 mL, 0.49 mmol) was added at 0 ° C., and stirred for 10 minutes. Water (5 mL) was added to terminate the reaction. The resulting solid was filtered under reduced pressure to give a white solid, which was dried under reduced pressure and purified by silica gel column chromatography (5% methanol / dichloromethane) to give 58 mg (0.16) of the target compound as a white solid. mmol, 62%).

Rf = 0.17 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 3.30 (m, 2H), 3.76 (s, 3H), 4.85 (t, 1H), 6.86 (d, 2H), 7.21 (d, 2H), 7.40 (dd, 1H), 7.74 (d, 1H), 7.92 (d, 1H), 7.94 (br-s, 1H), 9.11 (br-s, 1H), 9.48 (s, 1OH)

mass: 370 (-1), 233

Example  49: 2- [1- Methoxycarbonyl -3- (4- Methoxyphenyl ) Propylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

165 mg (0.85 mmol) was used instead of 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1 and methyl methyl-bromo-3-chlorophenyl acetate 179 mg of the target compound as a white solid by reaction in the same manner as in Example 1, except that 2-bromo-4- (4-methoxyphenyl) butyric acid methyl ester (245 mg, 0.85 mmol) was used. (0.45 mmol, 53%) was obtained.

Rf = 0.28 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.12 (m, 1H), 2.24 (m, 1H), 2.67 (m, 2H), 3.65 (s, 3H), 3.69 (s, 3H), 4.43 (t, 1H), 6.82 (d, 2H, J = 8.61 Hz), 7.12 (d, 2H, J = 8.61 Hz), 7.26 (dd, 1H), 7.57 (d, 1H), 7.75 (br-s, 1H), 7.78 (d, 1 H), 8.84 (br-s, 1 H), 13.15 (br-s, 1 H)

mass: 399

Example  50: 2- [1- Methoxycarbonyl -3- (4- Hydroxyphenyl ) Propylsulfanyl ] -1H- Benzimidazole -4- Carboxamide  Produce

Instead of using 200 mg of 2-mercapto-1H-benzimidazole-4-carboxamide in Example 1, 50 mg (0.26 mmol) was used instead of methyl α-bromo-3-chlorophenylacetate. Was reacted in the same manner as in Example 1, except that 2-bromo-4- [4- (t-butyldimethylsilyloxy) phenyl] butyric acid methyl ester (100 mg, 0.26 mmol) was used. 80 mg (0.16 mmol, 62%) of the title compound was obtained as a solid.

The compound obtained above (70 mg, 0.14 mol) was dissolved in purified THF (3 mL), and tetrabutylammonium fluoride (1M in THF) (0.08 mL, 0.28 mmol) was added at 0 ° C., and stirred for 10 minutes. Water (20 mL) was added and extracted with ethyl acetate (30 mL). The organic layer was washed with an aqueous NaCl solution, dried over MgSO ₄ , concentrated and purified by silica gel column chromatography (5% methanol / dichloromethane) to obtain 48 mg (0.12 mmol, 89%) of the title compound as a white solid.

Rf = 0.08 (5% MeOH / MC)

¹ H-NMR (300 MHz, DMSO) δ = 2.15 (m, 1H), 2.23 (m, 1H), 2.63 (m, 2H), 3.66 (s, 3H), 4.46 (t, 1H), 6.67 (d, 2H), 6.99 (d, 2H), 7.24 (dd, 1H), 7.58 (d, 1H), 7.71 (d, 1H), 7.76 (br-s, 1H), 8.90 (br-s, 1H), 9.18 (s, 1OH)

mass: 384 (-1), 202

The structures and substituents of the example compounds according to the invention are shown in Table 1.

EXAMPLES Structure and Substituents of Compounds Example rescue Substituent n X R ¹ R ² One

0 OCH ₃ 3-Br H 2

0 OCH ₃ 4-Br H 3

0 OCH ₃ 3-F H 4

0 OCH ₃ 4-F H 5

0 OCH ₃ 3-Cl H 6

0 OCH ₃ 4-Cl H 7

0 OCH ₃ 2-OCH ₃ H 8

0 OCH ₃ 3-OCH ₃ H 9

0 OCH ₃ 4-OCH ₃ H 10

0 OCH ₃ 4-OH H 11

0 OCH ₃ 3-CN H 12

0 OCH ₃ 4-CN H 13

0 OCH ₃ 4-CF ₃ H 14

0 OCH ₃ 4-OCF ₃ H 15

0 OCH ₃ 4-NO ₂ H 16

0 OCH ₃ 4-CHO H 17

0 OCH ₃ 3-OCH ₃ 4-OCH ₃ 18

0 OCH ₃ 2-OCH ₃ 6-OCH ₃ 19

0 OCH ₃ 3-OCH ₃ 5-OCH ₃ 20

0 OCH ₃ 4-CH ₂ OH H 21

0 OCH ₃ 4-CH ₂ NHCH ₃ H 22

0 OCH ₃ 4-CH ₂ N (CH ₃ ) ₂ H 23

0 OCH ₃

H 24

0 OCH ₃

H 25 0 OCH ₃

H 26

0 OCH ₃

H 27

0 OCH ₃

H 28

0 OCH ₃

H 29

0 OCH ₃

H 30

0 OCH ₃

H 31

0 OCH ₃

H 32

0 OCH ₃

H 33

0 OCH ₃

H 34

0 OCH ₂ CH ₃ 4-OCH ₃ H 35

0 O (CH ₂ ) ₂ CH ₃ 4-OCH ₃ H 36

0 OCH ₂ CH ₃ 4-Br H 37

0 O (CH ₂ ) ₂ CH ₃ 4-Br H 38

0 OH 4-OCH ₃ H 39

0 NH ₂ 4-OCH ₃ H 40

0 NH ₂ 4-Br H 41

0 OCH ₃ 3-F H 42

One OCH ₃ 4-F H 43

One OCH ₃ 4-Br H 44

One OCH ₃ 4-CH ₃ H 45

One OCH ₃ 3-OCH ₃ H 46

One OCH ₃ 4-OCH ₃ H 47

One OCH ₃ 4-NO ₂ H 48

One OCH ₃ 4-OH H 49

2 OCH ₃ 4-OCH ₃ H 50

2 OCH ₃ 4-OH H

The 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the general formula (1) according to the present invention were subjected to the following experiments to investigate various pharmacological actions.

Experimental Example  One : PARP -1 inhibitory effect measurement

In order to determine the PARP-1 inhibitory effect of the 2-sulfanyl-benzimidazole-4-carboxamide derivative of the present invention, the following experiment was performed.

This experiment was performed using the Universal Colorimetric PARP Assay-Histones kit (TREVIGEN, 4671-096-K). Dilute histones and coating buffers, concentrated 10-fold and 5-fold, with water to coat histone plates (Greiner, 781061, standard clear plate) with water, and dispense 25 μL of the mixture for each assay for 12 to 18 hours at 4 ° C. It was left for hours. Then, the solution remaining on the plate was removed at one time and washed four times with 1 × PBS (pH 7.4). In each experimental step, the solution was repeatedly removed and washed off, so that the solution of the previous step was not left on the plate. Paper towels were used to remove residual solution. 10 × Strep-Diluent was diluted with 1 × PBS (pH 7.4), 50 μL was dispensed for each assay, and left at room temperature for 2 hours. During the time of standing, the concentrated reagents required for the enzymatic reaction were diluted in the required amounts. Prepare 1X PARP buffer (20-fold concentrate diluted with water), 1X PARP cocktail (10-fold concentrated PARP cocktail and DNA diluted with 1X PARP buffer) on ice, and after time, remove the solution from the plate After washing four times with 1X PBS, enzyme reactions were mixed. The total volume of the reaction per each assay was 25 μL and 12.5 μL of 1 × PARP cocktail, 5 μL of test sample, and 7.5 μL (0.5 U) of PARP enzyme (diluted with 1 × PARP buffer) were mixed in this order. After reacting for 1 hour at room temperature, the solution was removed and washed 4 times with 1X PBS. 25 μL of Strep-HRP (Horseradish Peroxidase) diluted 500 × with 1 × Strep-Diluent was dispensed for each assay. After standing at room temperature for 20 minutes, it was removed and washed 4 times with 1X PBS. The remaining solution was completely removed and 25 μL of TACS-Sapphire (Peroxidase substrate) was dispensed for each assay. After reacting for 20 minutes in the dark, 25 µL of 0.2N HCl was added to stop the reaction. Absorbance was measured at 450 nm with a multilabel counter (Victor ² , PerkinElmer, Turku, Finland) within 30 minutes after addition of 0.2N HCl.

Initially, the inhibition rate at 10 μM was determined, and the IC ₅₀ value was obtained only for the drug inhibited by 50% or more.

Inhibition rate = [(high absorbance mean-drug absorbance) / (high absorbance mean-low absorbance mean)] * 100

Drugs inhibited by 50% or more were absorbed at concentrations of 0.01 to 10 μM, respectively, and IC ₅₀ was calculated through Excel-data analysis-regression analysis.

The measurement results are shown in Table 2 below.

Inhibitory Effects of Example Compounds on PARP-1 Example IC ₅₀ (μM) Example IC ₅₀ (μM) One 0.85 2 0.61 3 0.87 4 0.72 5 1.34 6 0.36 7 0.83 8 0.46 9 0.21 10 11.55 11 0.34 12 0.19 13 0.69 14 0.98 15 0.30 16 0.45 17 1.54 18 2.62 19 4.36 20 0.14 21 0.30 22 0.24 23 0.49 24 0.68 25 0.27 26 0.57 27 1.42 28 0.70 29 0.77 30 0.71 31 0.66 32 0.79 33 4.75 34 0.75 35 2.85 36 0.77 37 5.08 38 4.29 39 0.30 40 0.55 41 0.98 42 0.14 43 0.57 44 0.26 45 0.33 46 0.69 47 0.03 48 0.15 49 0.45 50 0.34

As shown in Table 2, the compounds of the examples of the present invention showed a generally excellent PARP-1 inhibitory effect, in particular 9, 12, 15, 20, 21, 22, 25, 39, 42, 47 and 48 compounds Showed an IC ₅₀ value of 0.3 μM or less, indicating a very good PARP-1 inhibitory effect.

Thus, the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the present invention exhibit potent inhibitory effects on PARP-1, leading to diseases caused by PARP-1 overactivity, i.e., ischemic diseases, neurons. It can be usefully used for degenerative diseases, and can be usefully used for cardioprotection in surgical or pharmacotherapy procedures.

Experimental Example 2: Rat in vivo Cardioprotection against ischemic heart model

To determine whether the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the present invention protect the ischemic heart in vivo , the antiischemic effect in rats (Antiischemic effects) Was investigated through the following experiment.

Male rats (350-450 g, Korea Research Institute of Chemical Technology) were anesthetized by intraperitoneal injection of pentobarbital at 75 mg / kg. After tracheotomy, artificial respiration was performed at a stroke volume of 10 mL / kg and a heart rate of 60 beats per minute. Cannula was inserted into the femoral vein and the femoral artery and used for drug administration and blood pressure measurement, respectively. On the other hand, in the ischemic myocardial injury model, the body temperature has a significant effect on the results, so that the temperature of the rat is constant at 37 ° C. using a probe inserted in the rectum and a homeothermic blanket control unit. Maintained. Since then, the mean arterial blood pressure and heart rate (HR) of the rat were continuously measured. At this time, the Statham P23XL pressure transducer (Statham P23XL pressure transducer, Grass Ins., MA, USA) was used, and the ECG / RATE Coupler, Hugo Sachs Electronic (Germany) was used to measure the heart rate. . In addition, all changes were recorded continuously using a Graphtec Linearcorder WR 3310, Hugo Sachs Electronic.

The left coronary artery was ligated by the method of Selye H. as follows. In other words, a part of the chest of the rat is opened by left thoracotomy, the pressure is applied to the right chest of the anesthetized rat with the left limb, and the heart is pushed outwards to lightly touch the heart with the thumb and index finger of the left hand. Fixed. The surgeon (5-0 silk ligature) attached to the suture (suture) and carefully carefully cut the part containing the left anterior desending coronary artery (LAD) and then quickly thoracic heart repositioned in the cavity and both ends of the surgeon were positioned externally. Both ends of the surgeon were allowed to pass through a PE tube (PE100, 2.5 cm) and left for 20 minutes to stabilize. Thereafter, a vehicle or a drug was administered through the cannula inserted into the femoral vein, and left for 30 minutes to fully exhibit the effect of the drug. At this time, the carrier was used as a drug carrier.

After that, the PE tube inserted into the thread was pushed into the heart, and the end thread of the tube was pulled with hemostatic tweezers, and the PE tube was pressed vertically to the coronary artery, and the pressure was left to remain for 45 minutes. After occlusion, hemostatic tweezers were removed and reperfused for 90 minutes.

The coronary artery was religated by the method and 2 mL of 1% Evans blue solution was administered intravenously. Pentobarbital was then intravenously administered to slaughter rats and the heart was removed to remove the right ventricle and both atria. The left ventricle was horizontally cut into 5-6 slices from the apex and the weight of each section was measured. The surface of each cardiac segment is input to a computer using a Hi-scope, a compact micro vision system, and an image pro plus, from which the blue Areas of normal blood flow tissue colored and uncolored areas were measured. The area ratio of the uncolored area was calculated for the total area of each section, and the weight of each section was multiplied to calculate the area at risk (AAR). The AAR for each section thus obtained was summed and divided by the total left ventricular weight to obtain AAR (%) by Equation 1 below.

In addition, cardiac sections were incubated for 15 minutes in 1% 2,3,5-triphenyltetrazolium chloride phosphate buffer solution (2,3,5-triphenyltetrazolium chloride (TTC) phosphate buffer, 37 ° C, pH 7.4) and Fixed in 20% formalin solution for 20-24 hours. In this way, 2,3,5-triphenyltetrazolium chloride is reduced by the dehydrogenase and cofactor NADH of the myocardium, thereby forming a formazan dye. (brick-red color). On the other hand, since there are no dehydrogenases and cofactors in the infarcts of tissues, 2,3,5-triphenyltetrazolium chloride is not reduced and thus does not have a red brick color.

As described above, the normal area and the infarct zone of each section were determined by the same method as in the AAR measurement, depending on whether or not the tissue site was colored by 2,3,5-triphenyltetrazolium chloride . The infarct regions for each of the sections thus obtained were summed and divided by the total AAR weight or the total left ventricular weight to obtain IS (%) by the following equation (2). In this experimental model, the lower the IS (%), the smaller the infarct area, and therefore, the anti-ischemic effect of the test substance was determined to be strong. The measurement results are shown in Table 3.

Example Antiischemic Effects of Compounds Example Myocardial infarction rate (IS / AAR ¹ ,%) One 1 mg / kg 45.2 2 1 mg / kg 48.7 6 1 mg / kg 49.0 8 1 mg / kg 49.0 9 1 mg / kg 30.0 10 1 mg / kg 43.2 34 1 mg / kg 44.7 38 1 mg / kg 32.4 39 1 mg / kg 46.7 Negative Control 58.6 1: IS / AAR (infacrt size / area at risk)

As shown in Table 3, in using the rat Even in the in vivo ischemic myocardial injury model, the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the present invention showed a significantly reduced myocardial infarction rate for the risk zone. Specifically, in the solvent-administered group, myocardial infarction (IS / AAR,%) was 58.6% for the risk area (AAR), indicating that myocardial damage due to ischemia is very severe. Example compounds subjected to myocardial infarction experiments showed a significant decrease of 58.6% of the negative control group at 1 mg / kg administration, especially the compounds of Examples 9 and 38 showed 30.0% and 32.4% myocardial infarction, respectively. It showed excellent cardioprotective effect.

Thus, the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the invention are in vivo It is excellent in protecting against ischemic heart by reducing myocardial infarction rate in ischemic heart model, and can be used as a preventive and therapeutic agent for ischemic heart disease such as myocardial infarction, arrhythmia and angina pectoris. It can be used as a cardioprotectant.

Experimental Example  3: On the rat  Acute toxicity test for oral administration

In order to determine the acute toxicity of the novel 2-sulfanyl-benzimidazole-4-carboxamide derivatives of the present invention, the following experiment was performed.

Acute toxicity test was performed using SPF SD rats at 6 weeks of age. Two animals per group were suspended orally at a dose of 10 mg / kg / 15 mL each of the compounds of Example 19 in 0.5% methylcellulose solution.

After administration of the test substance, the mortality, clinical symptoms and changes in body weight were observed, and hematological and blood biochemical tests were performed. The necropsy was performed to visually observe the abdominal and thoracic organ abnormalities.

As a result, all animals treated with test substance showed no clinical symptoms and no dead animals, and no toxicity change was observed in weight change, blood test, blood biochemical test, autopsy findings. As a result, all of the tested compounds did not show toxic changes up to 10 mg / kg in rats, and the minimum lethal dose (LD ₅₀ ) was determined to be a safe substance of at least 100 mg / kg or more.

On the other hand, the compound according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation example  1: Preparation of tablet (direct press)

5.0 mg of derivative compounds of the invention

Lactose 14.1 mg

Crospovidone USNF 0.8 mg

Magnesium Stearate 0.1 mg

After sifting the derivative compound of the present invention, lactose, crospovidone USNF and magnesium stearate were mixed and pressed to prepare a tablet.

Formulation example  2: Preparation of Tablets (Wet Granulation)

5.0 mg of the derivative compound of the present invention,

Lactose 16.0 mg

Starch 4.0 mg

Polysorbate 80 0.3 mg

Colloidal silicon dioxide 2.7 mg

Magnesium Stearate 2.0 mg

Distilled water

After sifting the derivative compound of the present invention, lactose and starch were mixed. After dissolving Polysorbate 80 in distilled water, an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with colloidal silicon dioxide and magnesium stearate. The granules were pressed to produce tablets.

Formulation example  3: Powder  Produce

5.0 mg of the derivative compound of the present invention,

Lactose 14.8 mg

10.0 mg polyvinyl pyrrolidone

Magnesium Stearate 0.2 mg

After sifting the derivative compound of the present invention, a powder was prepared by mixing with lactose, polyvinyl pyrrolidone and magnesium stearate and filling into an airtight cloth.

Formulation example  4: Preparation of Capsule

5.0 mg of the derivative compound of the present invention,

Lactose 14.8 mg

10.0 mg polyvinyl pyrrolidone

Magnesium Stearate 0.2 mg

After sifting the derivative compound of the present invention, it was mixed with lactose, polyvinyl pyrrolidone and magnesium stearate. The mixture was compressed into tablets according to a conventional capsule preparation method and filled into gelatin capsules to prepare gelatin capsules.

Formulation example  5: Preparation of Injection

100 mg of the derivative compound of the present invention,

Mannitol 180 mg

Na ₂ HPO ₄ 12H ₂ O 26 mg

Distilled water 2974 mg

The derivative compound of the present invention was dissolved in distilled water together with mannitol and Na ₂ HPO ₄ 12H ₂ O, sterilized by adjusting the pH to about 7.5, and then injections were prepared according to a conventional method.

Claims (15)

2-sulfanyl-benzimidazole-4-carboxamide derivatives of Formula 1 below or pharmaceutically acceptable salts thereof: [Formula 1]

In the above formula, R ¹ and R ² are each independently selected from the group consisting of hydrogen, halogen, NO ₂ , CN, CF ₃ , CHO, OR ³ , C ₁ to C ₄ linear or branched alkyl and CH ₂ Y, here, R ³ is hydrogen or a C _{1 ~} C ₄ linear or branched alkyl or CF ₃ in, Y is _{^{oR 3, NHCH 3, N (}} CH 3) 2,

,

,

,

,

And

Any one selected from the group consisting of wherein R ⁴ is hydrogen, halogen or OR ³ , and R ³ is as defined above; X is OH, OR ³ or NHR ³ ; n is an integer of 0-2. The method of claim 1, R ¹ and R ² are each independently hydrogen, fluoro, chloro, bromo, NO ₂ , CN, CF ₃ , CHO, hydroxy, methoxy, ethoxy, -OCF ₃ , CH ₂ OH, CH ₂ NHCH ₃ , CH ₂ N (CH ₃ ) ₂ ,

,

,

,

,

And

Any one selected from the group consisting of: wherein R ⁴ is hydrogen, fluoro, chloro or methoxy; X is any one selected from the group consisting of OH, methoxy, ethoxy, protoxy and amino; N is an integer of 0 to 2, and 2-sulfanyl-benzimidazole-4-carboxamide derivative or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the 2-sulfanyl-benzimidazole-4-carboxamide derivative is 1) 2- [methoxycarbonyl (3-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 2) 2- [methoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 3) 2- [methoxycarbonyl (3-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 4) 2- [methoxycarbonyl (4-fluorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 5) 2- [methoxycarbonyl (3-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 6) 2- [methoxycarbonyl (4-chlorophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 7) 2- [methoxycarbonyl (2-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 8) 2- [methoxycarbonyl (3-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 9) 2- [methoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 10) 2- [methoxycarbonyl (4-hydroxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 11) 2- [methoxycarbonyl (3-cyanophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 12) 2- [methoxycarbonyl (4-cyanophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 13) 2- [methoxycarbonyl [4- (trifluoromethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 14) 2- [methoxycarbonyl [4- (trifluoromethoxy) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 15) 2- [methoxycarbonyl (4-nitrophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 16) 2- [methoxycarbonyl (4-formylphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 17) 2- [methoxycarbonyl (3,4-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 18) 2- [methoxycarbonyl (2,6-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 19) 2- [methoxycarbonyl (3,5-dimethoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 20) 2- [methoxycarbonyl (4-hydroxymethylphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 21) 2- [methoxycarbonyl [(4-methylaminomethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 22) 2- [methoxycarbonyl [(4-dimethylaminomethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 23) 2- [methoxycarbonyl [(4-pyrrolidin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 24) 2- [methoxycarbonyl [(4-morpholin-4-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 25) 2- [methoxycarbonyl [(4-piperidin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 26) 2- [methoxycarbonyl [4- (4-methylpiperazin-1-ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 27) 2- [methoxycarbonyl [4- (4-phenyl-3,6-dihydro-2H-pyridin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide ; 28) 2- [methoxycarbonyl [4- [4- (4-chlorophenyl) -3,6-dihydro-2H-pyridin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole- 4-carboxamide; 29) 2- [methoxycarbonyl [4- (4-phenylpiperazin-1 ylmethyl) phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 30) 2- [methoxycarbonyl [4-[(4-fluorophenyl) piperazin-1 ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 31) 2- [methoxycarbonyl [4-[(2-methoxyphenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 32) 2- [methoxycarbonyl [4-[(3-methoxyphenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 33) 2- [methoxycarbonyl [4-[(2-chlorophenyl) piperazin-1ylmethyl] phenyl] methylsulfanyl] -1H-benzimidazole-4-carboxamide; 34) 2- [ethoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 35) 2- [propoxycarbonyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 36) 2- [ethoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 37) 2- [propoxycarbonyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 38) 2- [carboxy (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 39) 2- [carbamoyl (4-methoxyphenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 40) 2- [carbamoyl (4-bromophenyl) methylsulfanyl] -1H-benzimidazole-4-carboxamide; 41) 2- [1-methoxycarbonyl-2- (3-fluorophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 42) 2- [1-methoxycarbonyl-2- (4-fluorophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 43) 2- [1-methoxycarbonyl-2- (4-bromophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 44) 2- [1-methoxycarbonyl-2- (4-methylphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 45) 2- [1-methoxycarbonyl-2- (3-methoxyphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 46) 2- [1-methoxycarbonyl-2- (4-methoxyphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 47) 2- [1-methoxycarbonyl-2- (4-nitrophenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide; 48) 2- [1-methoxycarbonyl-2- (4-hydroxyphenyl) ethylsulfanyl] -1H-benzimidazole-4-carboxamide 49) 2- [1-methoxycarbonyl-3- (4-methoxyphenyl) propylsulfanyl] -1H-benzimidazole-4-carboxamide; And 50) 2- [1-methoxycarbonyl-3- (4-hydroxyphenyl) propylsulfanyl] -1H-benzimidazole-4-carboxamide; 2-sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, characterized in that any one selected from the group consisting of: As shown in Scheme 1 below, ² -sulfanyl-benz comprising the step of alkylating the compound of formula (2) as a starting material under the reaction solvent to obtain a compound of formula (1) having X, R ¹ and R ² introduced therein. Process for the preparation of imidazole-4-carboxamide derivatives. Scheme 1

(In the above scheme, n, X, R ¹ and R ² are as defined in formula (1), and L is any one leaving group selected from the group consisting of halogen element, mesylate and tosylate.) The preparation of 2-sulfanyl-benzimidazole-4-carboxamide derivative according to claim 4, wherein the compound of Formula 3 is used in an amount of 1 to 3 equivalents based on the compound of Formula 2 in the presence of a base catalyst. Way. The method of claim 5, wherein the base catalyst is carbonate comprising sodium carbonate, potassium carbonate or cesium carbonate; Hydroxides including potassium hydroxide or sodium hydroxide; Hydrides including sodium hydride; Alkoxides including sodium methoxide, sodium t-butoxide; Triethylamine; And pyridine; any one or more inorganic or organic bases selected from the group consisting of pyridine. 2. A process for producing 2-sulfanyl-benzimidazole-4-carboxamide derivatives. The method of claim 4, wherein the reaction solvent is dimethylformamide; Dimethyl sulfoxide; Ether solvents including tetrahydrofuran or dioxane; Acetone; Acetonitrile; Aromatic hydrocarbon compound solvents including benzene or toluene; Halogenated hydrocarbon compound solvents including dichloromethane or chloroform; water; And any one or a mixed solvent thereof selected from the group consisting of acetic acid. 2. A process for producing 2-sulfanyl-benzimidazole-4-carboxamide derivatives. The method of claim 4, wherein the reaction is carried out at room temperature from the boiling point of the solvent to room temperature. delete delete The group consisting of myocardial infarction, angina pectoris, arrhythmia, heart failure, stroke, brain trauma and renal failure containing the 2-sulfanyl-benzimidazole-4-carboxamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for preventing or treating a disease selected from. delete Prevention of a disease selected from the group consisting of Parkinson's disease, Alzheimer's disease and multiple sclerosis comprising the 2-sulfanyl-benzimidazole-4-carboxamide derivative of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient Or therapeutic pharmaceutical compositions. delete delete